The ribosome implements the genetic code by translating information residing in nucleic acid into protein, a process which lies at the heart of all organisms. Within the translational cycle, the decoding step distinguishes the ribosome from other molecular machines. During this step, the ribosome must discriminate between correct and incorrect transfer RNAs, accepting only those whose amino acid corresponds to the messenger RNA codon, as prescribed by the genetic code. Recent x-ray structural data has unveiled the local and global conformational changes involved in correct transfer RNA recognition by the ribosome;however, the order of events and cause-effect relation between local and global changes is not clear. We will use large-scale all-atom molecular dynamics simulations, validated by biochemical and x-ray data, to study the relation between local decoding interactions and large-scale conformational changes of the small ribosomal subunit. In particular, (1) We will use large-scale computer simulations to investigate the relative importance of codon-anticodon-ribosome hydrogen bonds at the decoding center on the open-to-closed conformational change of the small ribosomal subunit. Predictions based on these simulations will be tested biochemically. (2) We will use replica exchange molecular dynamics to investigate the flipping out of the decoding bases, A1492-A1493, from small subunit helix 44 in the presence of cognate tRNA, near-cognate tRNA, aminoglycoside antibiotics and resistance mutants. We will again compare with antibiotic-oligo binding. (3) We will investigate the order of events during tRNA recognition, in atomic detail, by testing whether the above base-flipping induces the open-to-closed conformational change of the small ribosomal subunit, with and without, decoding antibiotics. As alternative strategies, We will (1) improve sampling by using a mesoscale model, which couples small scale simulations of the decoding center, to information obtained from large scale simulations, (2) Perform all-atom normal mode calculations to study the effect of decoding base flipping and antibiotics on the overall motion of the ribosome, and (3) Attempt to modify force field potentials, by slightly modifying the delta gamma and epsilon torsional parameter coefficients. Our simulations will serve as a template for other researchers to perform million atom simulations. We will directly address the issues of time scale limitations, kinetic trapping and force field accuracy, with enhanced sampling simulation techniques and iteration between experimental data and simulation.